Dean of Arts and Sciences Joanne Berger-Sweeney presented her research on neurological disorders last Friday at the first installment of "A Taste of Tufts: A Sampling of Faculty Research," a weekly lecture series organized by the Experimental College.
Berger-Sweeney is a well-known neuroscientist who came to Tufts in August 2010 from Wellesley College. Her research focuses on memory and learning and how they malfunction in disorders such as Alzheimer's disease and Rett syndrome.
Entitled "How Understanding Brain Development Will Aid in Treating Rett Syndrome," Berger-Sweeney's talk began with a playful warning that this was her first scientific lecture for a general audience in years before delving into a discussion of her research into Rett syndrome.
Rett syndrome, which primarily affects girls, is considered a regressive development disorder that is part of the autism spectrum and occurs in about one in 10,000 children, according to Berger-Sweeney.
In girls who have Rett syndrome, development is normal until six to eighteen months, and then there is a rapid regression period from about one to three years of age. During this time, there is a loss of purposeful movements, which are replaced with repetitive movements such as hand-wringing. Other symptoms Berger-Sweeney cited included decelerated head growth, emotional disturbances, difficulty walking and mental retardation. Adulthood brings accelerated decline, with high incidence of osteoporosis, scoliosis and motor deterioration. The average life expectancy for a woman with Rett syndrome is in the mid-40s.
The vast majority of Rett syndrome cases are associated with spontaneous mutations in a gene in the X chromosome called the methyl-CpG-biding protein 2 (MeCP2) gene, Berger-Sweeney said. Normally, the MeCP2 gene provides instructions for making a protein that binds to DNA and prevents genes from being transcribed. Those afflicted with Rett syndrome do not have sufficient amounts of this important protein, according to Berger-Sweeney.
"Genes that are normally not activated or activated for a while and then shut down are going to be on all the time," she said. "Most of what we see from Rett syndrome is with genes that are on more than they should be."
She explained that scientists do not understand exactly why this results in the abnormalities of Rett syndrome.
When the gene associated with Rett syndrome was discovered in 1999, it was possible to create animal models that had the same type of genetic mutation. Berger-Sweeney recounted that in 2001 she read an article in Science magazine revealing Rudolf Jaenisch, a biologist at the Massachusetts Institute of Technology, had created a mouse model with a mutation in MeCP2.
"After I read the article, I called and emailed him. I wanted to see this mouse, and how carefully or similarly it produced Rett syndrome. It took multiple calls and emails to Rudolf Jaenisch's secretary, until I finally spoke to him and he said he would be more than happy to give me some of the mice," she said.
Berger-Sweeney received the mice from Jaenisch in 2003. With the help of undergraduate students at Wellesley College, she looked at the physical and sensory characteristics of the mice, including their motor skills, anxiety levels, sociability, cognitive ability and life span, to check for the same symptoms found in girls with Rett syndrome.
This task, Berger-Sweeney said, was difficult and time-consuming.
"It took about six years of characterization. It takes a long time to do this, you have to do it with lot of animals and have to make sure you are able to repeat what you're doing. It was not easy," she said.
"What was so interesting is when we got the animals and started breeding them in our labs, we saw the mice doing the hand wringing motion. We saw how they were moving and walking, and my best guess was data would recapitulate symptoms of Rett syndrome," Berger-Sweeney said.
Indeed, the mice displayed many symptoms that are seen in humans with Rett syndrome. However, the male mice appeared to recapitulate Rett syndrome symptoms better than the female mice.
"If you think about a male, with one X and one Y chromosome, it means a male that has the mutation has no protein, where females have one mutated and one normal," Berger-Sweeney said. "In females, some cells aren't producing proteins and some are. Thus, the null male appears to recapitulate better than the females that are heterozygotes."
According to Berger-Sweeney, one possible underlying cause of Rett syndrome is the reduced functioning of the cholinergic system early in development.
Berger-Sweeney is particularly interested in the cholinergic system — a system of nerves that uses acetylcholine as its neurotransmitter — and the development of the brain.
Her original hypothesis was that acetylcholine is extremely important for the progress of the cerebral cortex early in development. She theorized that something that boosted the cholinergic system at birth would reduce the initial symptoms of Rett syndrome.
In 2009, she was contacted by a drug company in Italy asking if her lab would be interested in using their cholinergic compound, acetyl-L-carnitine, in the mouse model to see whether it had an impact on Rett syndrome. She decided to give it a try.
"We basically took the animals from birth and injected the medicine every day until the end of experimentation," Berger-Sweeney said. "We looked at various factors, including motor function and cognitive function, and looked at chemical factors after the mice died."
Berger-Sweeney saw that impaired mice who received the drug treatment showed significant cognitive improvement — the first such observation in animals with the Rett mutation, she said.
Berger-Sweeney, who has not yet published the data, added that the drug seemed to make the mice look normal for about 30 days before the symptoms of Rett syndrome became visible.
"My hypothesis that the cholinergic system has something do with performance is part of it, but it is not the whole story," she said. "However, we did demonstrate that the drug is capable of improving cognitive performance if you do it early."
